To date we have generated mice with Gq/11-alpha deficiency in the paraventricular nucleus of the hypothalamus (PVN) using Sim1-cre transgenic mice. These mice develop severe obesity associated with hyperphagia with no change in energy expenditure or in glucose metabolism. They also show a defect in the ability of a melanocortin 4 receptor (MC4R) agonist (MTII) to inhibit food intake acutely. We confirmed that MC4R can activate Gq/11-alpha in PVN. These findings suggest that MC4R inhibits food intake via a Gq/11-alpha pathway in the PVN. Similar results were obtained by injecting AAV-cre directly into PVN of Gq-floxed/G11-alpha deficient mice. In contrast the cardiovascular effects of MC4R in PVN are mediated by Gs-alpha. Moreover, Gq/11-alpha signaling is important in regulation of the hypothalamic-pituitary-adrenal axis. We are presently studying various human MC4R mutations to examine their signaling properties and the mechanisms by which they lead to obesity. We also knocked out Gq/11-alpha in adipose tissue using aP2-cre and adiponectin-cre transgenic mice and see no major phenotype, in contrast to what we see after knocking out Gs-alpha using this same cre-transgenic line (DK043316). We are also knocking out Gq/11-alpha in liver. In a collaboration it was shown that Gq/11 signaling is also important for chondrocyte differentiation. Prelimary results also show that G11-alpha knockout mice are resistant to diet-induced obesity. We are presently trying to generate G11-alpha floxed mice. Preliminary evidence shows that Gq/11-alpha signaling in the dorsomedial hypothalamus is important in energy balance and in browning of white adipose tissue in mice.